More than 43.0% of all HD cases were diagnosed with more than 59 years, being the mean age of testing 52.2 years-old, which confirms the late onset of the HD [2, 16], with no differences between men and women.
Based on the total population served by the Clinical Genetics Section of the HUMS the overall incidence was 64.8 per 100 000 patient-years, no differences were found between men and women. In addition, taking into account the different study periods, similar values were obtained (66.8 in 2007-2012 and 63.1 in 2013-2019).
A few years earlier, in the Basque country and Navarre in Spain (geographical areas adjacent to our community), Ramos-Arroyo et al. determined an incidence of 48 and 46 per 100 000 patient-years respectively [14], being lower than the incidence found in our population.
In other European countries, the incidence rates calculated were the following, all of them per 100 000 person-years: 0.3 in the province of Ferrara, northern Italy (1990-2009) [17]; 1.8 in Germany (2015-2016) [18]; 0.14 in Iceland (1988-2007) [19]; the minimum incidence rate was 0.22, being able to reach 0.44 in Greece (1995-2008) [20]; 0.25 in Cyprus (1984-2015) [21]; and 0.72 in United Kingdom (1990-2010) [22]. So, the incidence of HD varies from 0.14 to 1.8 per 100 000 person-years in Europe.
In the population of the United States from 2003 to 2016 the incidence rate was 1.22 per 100 000 person-years [23] while in Asian countries it is much lower (0.06 in Korea during 2009-2013 [24] and 0.1 in Taiwan during 2000-2007 [25]). In their review, Pringhsheim et al. found a mean incidence of 0.4 per 100 000 person-years. Studies including non-Asian population has a higher incidence (0.1-0.8) than studies with Asian descent populations (0.05-0.1) [26]. No incidence studies have been found in the African population [27], although the prevalence of HD in sub-Saharan areas and southern Africa has been found to be lower than in populations of Caucasian origin [27–29].
The incidence in Aragon is higher than the reported for other Caucasian populations, although exists an apparent heterogeneity that varies both time and place. Indeed, this heterogeneity appeared in the estimations of the HD prevalence too, being lower in studies carried out in Asia and Africa than in those that include predominantly populations of European descent [22, 27, 29]. Differences in diagnostic criteria and case ascertainment could explain this variety. Also, if pre-symptomatic cases were included, to the proportion of individuals opting for a predictive testing, which would increase the number of cases. Since the early 1990s for the HD mutation exists a molecular genetic test for its diagnostic. This way, depending on its availability in the different geographical regions, the estimate of new cases may vary. Finally, some authors have suggested the presence of modifiers of the expression of the disease (genetic or environmental) that could play an important role in the expansions of the HD allele around the world, what would make the population more or less prone to the disease [30, 31].
Given that the genetic mutation presumably originated in north-western Europe [26], it suggests that there could be a founder effect in Aragon. This would be possible since the incidence is so high in this region compared to other European populations, but more similar to the Basque Country and Navarra, neighbouring communities also located in north-eastern Spain. However, it would be necessary to carry out more extensive studies for its confirmation.
This complex landscape contributes to an uncertain epidemiology for HD and incidence rates are probably underestimated despite the progress in the knowledge of this disease in recent years [17].
The most common CAG length in our population among the normal alleles was 16, slightly lower than the length found in European population with 17 CAGs repeats [7]. In Danish population, this size is the most frequent too [32], as well as for Canadians [33].
The mean size of 17.2 (SD 2.8) repeats for Aragonese people was similar to that found in European population, being larger compared to the mean size in Asian countries such as China, Japan and Thailand (16.4, 16.6 and 16.5 repeats respectively) [24]. In Latin America the mean varies from 15 to 17.8 repeats, similar to those reported among Caucasians an Asians [34], being 16 the most common repeat among HD negative individuals in Cuba and 17 in Venezuela [35].
These variations in the normal range of CAG repeats according to the population studied (greater for countries whose offspring are of Caucasian origin than in those of Asian origin) correspond to those observed in the incidence and prevalence of the HD, since both are directly related [34]. In populations with high prevalence of HD is higher the number of CAG repeats in normal chromosomes [35].
Planning a family and prevention of passing on an expanded CAG-repeat to future offspring are the main reasons to apply for prenatal or preimplantation genetic diagnosis [36]. In our population, four prenatal and one preimplantation tests were carried out for 4 mothers affected of HD. In these cases, the importance of genetic counselling was revealed, being necessary the translation of the advances in genetic and in-utero techniques into genetic counselling, taking into account the ethical and scientific principles allowing families to make decisions, including the interruption of pregnancy [37], as one of our cases. It is important because younger generations are likely to be more seriously affected by inheriting a CAG repeat amplification, so the detection of the disease and prenatal tests would make it possible to inform and counsel other family members [14].
The frequency of IA in our population was 2.3%, similar to other general populations being observed in 1-7%, which can be considered commonly present [36]. The 42.3% of cases in this range presented clinical symptoms. Some years ago, IAs were not considered associated with symptomatic HD. Nevertheless, nowadays there is evidence that some individuals with IAs express the disease phenotype, developing HD-like clinical and neuropathological manifestations, as in our study, being more notable in older patients or in those with greater repeats within the range 27-35 [8].
When IA has more than 30 repeats, the probability that an expanded allele could be transmitted to the offspring is higher, being able to reach full penetrance [7]. In addition to the size of CAG, the likelihood of expansion to the disease associated range is highly influenced by the sex of the transmitting parent, being the majority of new mutations of paternal transmission [38], although also could be inherit by maternal line [9]. This explains our only confirmed case of a new mutation in which the father with 33 CAG repeats has been responsible for the transmission of the disease to his son (Patient 2) in the range of complete penetration.
This way during meiosis, IA instability results in de novo expansions, an uncommon but well-known source of new HD cases in individuals with no family history. The minimum new mutation rate for HD in our population was 2.0%, below the new mutation rate for the Basque country and Navarre with a minimum of 4.7% and a potential rate of 8.1% [14], although the new mutation rate for HD is estimated to be 10.0% [39]. In these patients, the negative family history of HD observed could be explained by new mutations, but also it could be due to misdiagnosis in family members, non-penetrance or non-paternity [20]. So further studies will be needed to confirm these findings, including genetic testing of family members even those asymptomatic ones. This fact is important information to take into account when genetic counselling a family with a true de novo HD case [40].
The main limitations of the study were found in the calculation of the de novo rate of new mutations, since in two patients their relatives could not be genetically tested. In addition, the association of clinical symptoms in those patients with IA is controversial. Other diseases with the same type of symptoms should be studied in order to be able to firmly affirm that this symptomatology is due to the presence of these alleles. Finally, the incidence has been calculated with reference to the population that belongs to our health sector, but it may be neglecting patients who, even belonging to this area, have carried out the study elsewhere.